Brit. _. Ophthal. (I975) 59, I55

Solitary choroidal metastasis from bronchial carcinoid

R. M. BELL, J. D. BULLOCK, AND D. M. ALBERTDepartment of Ophthalmology and Visual Science, rale University School of Medicine, New Haven, Conn.

Carcinoid tumours are low-grade adenocarcinomaswhich originate from Kultschitzky cells of theenterochromaffin system. Although most frequentlyfound in the gastrointestinal tract, carcinoid mayarise from any enterochromafflin tissue. A commonlocation of primary carcinoid is the lung; and aboutio per cent. of these carcinoids metastasize. Therehave been only two previous reports (Font, Kaufer,and Winstanley, I966; Rosenbluth, Laval, and Weil,I960) of carcinoid metastasizing to the choroid; bothtumours originated in the lung. This paper reports amuch more extensively documented third case ofbronchial carcinoid metastatic to the choroid, withchest x rays, histopathology of the original lungtumour, fundus photography, fluorescein angio-graphy, ultrasonography, radio-isotope data, electronmicroscopy, and gross and microscopical photographsof the choroidal tumour.

Address for reprints: Robert MI. Bell, Departimient of Ophthalnmologyand Visual Science, Eye Pathology Laboratory, Yale UniversitySchool of Medicine, 333 Cedar Street, New Haven, Conn. 06510, U.S.A.

This study was supported by U.S.P.H.S. Grant EY-00108-4,U.S.P.H.S. Grant EY-00785-03, and the Connecticut Lions EyeResearchi Foundation, Inc.

FIG. I(a) Postero-anterior chest x ray taken inSeptember, 1970, showing lobulated lemon-sized righthilar mass

Case report

A 29-year-old white woman had been in good healthuntil September, 1970, when she developed a dry, non-productive cough and a low-grade fever. A chest x rayshowed a lobulated right hilar mass (Fig. Ia, b), initiallythought to be suggestive of Hodgkin's disease or sarcoidosis.The findings on general physical examination and thelaboratory data, including haemogram, urine analysis,liver function tests, and serum protein electrophoresis,were within normal limits. Frozen sections of bilateralscalene node biopsies failed to reveal any abnormality.However, upon right anterior thoracotomy, a multilobu-lated lemor-sized tumour was found in the right hilum. Abi-lobectomy of the two lower lobes of the right lung wasdone. Frozen sections showed the tumour to be a bronchialcarcinoid; histopathological sections indicated that thetumour was completely excised. Tumour cells were found,however, in one hilar lymph node (Fig. 2), and specialstains revealed them to be argyroplhilic.The patient remained asyrnptomatic until December,

1972, when she noted the onset of "flashbulb-like sensa-tions" in the left eye lasting for several seconds and recur-ring four or five times a day. Although she denied anyconmplaints suggestive of systematic carcinoid and othersignificant symptomatology, she was investigated inFebruary, 1973, for recurrence of the tunsour or nieta-stases.

FI G. I (b) Lateral view, showing mass

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FIG. 2 Photomicrograph of section through primary tumour, showing cord-like arrangement of cells, plump nuclei, andmultiplefine nucleoli typical of carcinoid. Haematoxylin and eosin. x 320

ExaminationThis was unremarkable except for the ocular findings. Theuncorrected visual acuity was 20/20 in each eye, and refrac-tion showed her to be essentially emmetropic. Findings onexternal examination were entirely within normal limits,as were slit-lamp examination, ocular tensions by applana-tion, and gonioscopy. Ophthalmoscopy of the right eye wasunremarkable; however, in the left there was a sharplydemarcated, 4 disc diameter, dome-shaped, whitish-

FIG. 3 Fundus photograph of left eye, showing choroidalmass with overlying retinal detachment

yellow lesion temporal to the fovea, with an overlyingserous detachment of the neurosensory retina (Fig. 3).

Central and peripheral fields of the right eye were fullon Goldmann and tangent screen perimetry. In the lefteye central field examination showed a sloping nasaldefect, and peripheral field examination demonstrated a 5disc diameter dense nasal scotoma corresponding to thelesion. Radio-isotopic scanning utilizing P32 resulted instatistically significant higher counts in the left eye atboth 24 and 48 hrs. Fluorescein angiography demonstrateda 4 disc diameter raised oval lesion which blocked fluores-cence centrally but was bordered by a ring of hyper-fluorescence, thickest inferotemporally (Fig. 4a, b). In thelater stages of the angiogram the mass stained diffusely.Ani overlying detachment of the neurosensory retina wasevident. Ultrasonography showed a mass with a base 7mm in diameter, elevated 41 mm. The lesion was acous-tically solid and failed to show evidence of choroidalexcavation, as is usually seen with a melanoma. Theretrobulbar echo pattern was interpreted as normal.Hence, the clinical appearance as well as the radio-isotopic scanning, fluorescein angiography, and ultrasono-graphy data were consistent with either choroidal mela-noma or a metastatic choroidal lesion, probably carcinoid.Normal laboratory studies included haemogram, electro-

lytes, serum calcium, serum phosphorus, serum iron, ironbinding capacity, VDRL, urine analysis, Pap smear, liverfunction tests, thyroid function tests, fasting blood sugar,chest x ray, bone scan, brain scan, liver scan, spleen scan,and 24-hour urinary 5-hydroxylin-dolacetic acid.

ProgressDuring the next 4 weeks the symptoms of retinal detach-ment became more frequent. The best corrected visual

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Solitary choroidal metastasis from bronchial carcinoid I57

(b) late staining (30 min.)FIG. 4 Fluorescein angiograms demonstrating blockedfluorescence centrally with ring of hyperfluorescence (a) withsubsequent diffuse staining of the mass (b)(a) arteriole phase (iO-I 2 sec.)

acuity in the left eye had deteriorated to 20/50, the neuro-sensory detachment had extended closer to the macula,and the underlying mass appeared larger. Diagnosis ofboth choroidal melanoma and carcinoid were considered.

OperationEnucleation was carried out.

At the time of this report 3 years have elapsed sinceremoval of the primary tumour and 15 months sinceenucleation, and the patient remains asymptomatic.

HISTOPATHOLOGICAL FINDINGS

(ross examinationAfter enucleation the globe was fixed immediately inphosphate-buffered 5 per cent. glutaraldehyde at 40C. forI hr. An area of decreased transillumination was presenttemporal to the optic nerve. A 2 x 3 x 2 mm. elevated,pearly-white choroidal tumour was noted temporal to the

FI G. 5a, b Photographs of sectioned globe revealing white choroidal tumour temporal to optic nerve. x 2 5

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optic nerve; the surrounding retina was slightly detached(Fig. 5a, b). The remainder of the findings on grossexamination were within normal limits.A i mm. thick slice of tissue through the tumour was

postfixed in phosphate-buffered osmium tetroxide andprocessed for electron microscopic examination.

Light microscopyThe cornea, anterior chamber, angle, iris, ciliary body,lens, vitreous, optic nerve, and sclera were normal. Alarge, unencapsulated, well-circumscribed tumour waspresent in the posterior choroid, temporal to the macula.The tumour was composed of uniform cells, round to ovalin shape, containing a moderate amount ofpink cytoplasm

with well-defined cellular outlines. The tumour cells con-tained plump nuclei and multiple fine nucleoli; raremitotic figures were present. The cells were arrangedin cords and ribbons, groups occasionally forming tubularstructures; many vascularized fibrous septa were present.In some areas the tumour had dissected into the superficialsclera and in other areas it appeared to compress theposterior choroid. Blood vessels temporal and nasal to thetumour were engorged and the choroid appeared oedema-tous. The retinal pigment epithelium (RPE) appearednecrotic with loss of cells nasally and temporally. Therewas in addition marked fibrous metaplasia of the RPEoverlying the tumour. In areas between the RPE andneural retina chronic inflammatory cells were noted. The

FIG. 6(a) Medium-power microscopic view qf tumour, showing necrosis of retinal pigment epithelium nasally and temporallyand its marked metaplasia overlying the tumour. There is cystoid degeneration and serous detachment of the neural retina x 42.

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FIG. 6(b) High-power view of tumour cells, showing well-vascularized arrangements of cords and tubular structures. x 260

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Solitary choroidal metastasis from bronchial carcinoid I59

neural retina overlying the tumour had undergone severecystoid degeneration with prominent loss of the photo-receptor and ganglion cells. A serous detachment of theneural retina surrounding the tumour was present (Fig.6a, b). In the area between the disc and the tumour theinternal limiting membrane was severely wrinkled withunderlying cystic spaces containing amorphous material.Silver staining by the Fontana-Masson method was posi-tive for argentophilia.The pathological diagnoses were bronchial carcinoid

metastatic to the choroid with a secondary serous retinaldetachment.

Electron microscopySome of the ultrastructural findings were similar to pre-vious descriptions of carcinoid tumours (Bensch, Gordon,and Miller, I965a; Black, I968; Gmelich, Bensch, andLiebow, I 967; Luse and Lacy, I 960; Toker, I 966). In con-trast to the uniform staining appearance of the tumourcells at the light microscopic level, electron microscopydemonstrated light and dark cell types (Fig. 7). There wasa large nucleus to cytoplasm ratio. The nuclei of both celltypes were round to ovoid and contained coarsely clumpedchromatin adjacent to the nuclear envelope. Large nucleoliwere prominent and occasional cells contained two nuclei.The scant cytoplasm contained abundant rough endo-plasmic reticulum. Small, round mitochondria appearedthroughout the cytoplasm, but several areas of tightlypacked mitochondria suggested polarization of some of thetumour cells. Also present throughout the cytoplasm, andoccasionally in clusters around the cell periphery, werecharacteristic neurosecretory granules. These granuleswere bounded by a unit mernbrane and consisted of anelectron dense core surrounded by an electron lucent zone(Fig. 8). The Golgi apparatus was not prominent. The

cytoplasm ofmany cells contained distinct, finely dispersedfibrils. There were few interdigitations of plasma mem-branes of adjacent tumour cells. However, numerousintercellular spaces and channels with projecting micro-villi coursed between cells (Fig. ga). In some areas thesechannels widened to form a gland-like structure; here themicrovilli were arranged in an orderly fashion (Fig. gb).The lumen of these "glands" contained dense fibrils andoccasional free neurosecretory granules. No granules wereobserved in the capillary endothelial cells of the connectivetissue stroma.

DiscussionBronchial adenomas were first described histologicallyby Muller (I882). Kramer (1930) first used the term"bronchial adenoma" to distinguish a type of tumourwhich was more benign, in behaviour and mor-phology, than bronchogenic carcinomas. Hamperl(I937) subsequently subdivided bronchial adenomasinto two groups, the most common of which he feltresembled intestinal carcinoid. The other group hedescribed as cylindromas because oftheir resemblanceto salivary gland tumours. These classifications arestill used, although a third type, "mucoepidermoid",has been added. For some time there was great dis-agreement whether the carcinoid-resembling tumoursof the lung were related to the carcinoid tumours ofthe gastrointestinal tract. The main reason why thesetumours were thought to be unrelated was that therewere histological differences, notably a lack ofargentaffinity in the bronchial carcinoid. Also, thecarcinoid syndrome, first described in depth byThorson, Biorck, Bjorkman, and Waldenstrom ( 954),

FIG. 7 Electron micrograph of typical light and dark cell types. Note cell containing two nuclei. x 37,000

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FIG. 8 Ultrastructure of neurosecretory granules. An electron dense core bounded by a unit membrane is evident in thegranules shown here (some in a cluster) at the cell periphery. x 42,000

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F I G. 9(b) Another widening of anintercellular channel forms a gland-like structure containing an orderlyarray of microvilli. Here the lumencontains dense fibrils. x I I,250

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was found initially only in association with malignantcarcinoid tumours of the gastrointestinal tract, and itwas not until 1956 that the first cases of carcinoidsyndrome associated with bronchial carcinoid werereported (Kincaid-Smith and Brossy, I956). It is nowgenerally accepted that carcinoid tumours arise fromKultschitzky cells of the enterochromaffin system.Recent electron microscopical studies (Bensch,Gordon, and Miller, I965b; Bensch, Corrin, Pariente,and Spencer, I968; Gmelich and others, I967) havedemonstrated Kultschitzky-type cells in bronchialepithelium wedged between the basal parts of thecolumnar epithelium which lines the bronchial ductsand glands.

In various series (Donahue, Weichert, and Ochsner,I968; Ochsner, Seymour, and Ochsner, I957; Tooleand Stem, I972; Turnbull, Huvos, Goodner, andBeattie, I972), bronchial adenomas were found tocomprise from i to I0 per cent. of all primary pul-monary tumours. Carcinoid accounts for 8o to 85 percent. of these bronchial adenomas, and cylindromasabout I2 to I5 per cent. (Batson, Gale, and Hickey,I966; Goodner, Berg, and Watson, I96I; O'Grady,McDivitt, Holman, and Moore, 1970; Toole andStem, 1972; Turnbull and others, 1972; Wilkins,Darling, Soutter, and Sniffen, I963). In generalabout I0 per cent. of bronchial adenomas havemetastases (McBurney, Kirklin, and Woolner, I953),although in one study (Goodner and others, I96I) 44per cent. of the patients had metastases at the time ofoperation. With carcinoid, the incidence ofmetastasesappears to be related to the type and histology(O'Grady and others, 1970; Pearson and Fitzgerald,I949; Tumbull and others, 1972; Wilkins and others,I 963), the degree ofanaplasia (Arrigoni, Woolner, andBematz, 1972; Bensch and others, I 968; Goodner andothers, 196I; McBumey and others, I953), and thesize of the primary tumour (Barclay and Robb, I 968;Moertel, Sauer, Dockerty, and Baggenstoss, 196I;Teitelbaum, I972). Cylindromas metastasize threetimes as frequently as carcinoid (McBurney andothers, I953). Several studies of patients with carci-noid tumours of the gastrointestinal tract have founda high frequency, 25 to 40 per cent. of a secondprimary tumour (Kuiper, Gracie, and Pollard, I970;Martin, I 970; Moertel and others, I96 I; Pearson andFitzgerald, I949; Teitelbaum, I972). This finding hasnot yet been confirmed for bronchial adenomas.

TreatmentAs with most malignant neoplasms, the treatment ofchoice for carcinoid is wide resection of the primarygrowth with removal of local lymph nodes and anyaccessible metastases (Bargen, I96I; Batson andothers, I966; Brindley and Bonnet, I967; Davies,1959; Ochsner and others, 1957; O'Grady and others,1970; Overholt, Bougas, and Morse, 1957; Pearsonand Fitzgerald, 1949; Smith, I 969; Teitelbaum, I 972;

Weisel, Lepley, and Watson, 196I; Wilkins andothers, I963). It is significant that, for patientsreceiving this treatment a relatively good prognosishas been reported (Batson and others, I966; O'Gradyand others, 1970; Overholt and others, I957; Wilkinsand others, I963). Chemotherapy is generallyreserved for patients with widespread, inoperablemetastases or with carcinoid syndrome, which mostfrequently develops after the primary tumour hasmetastasized to the liver (Bargen, I96I; Hill, I971;Oates and Butler, I967). In the latter case therapyusually consists of hormonal antagonists or sympto-matic treatment of the diarrhoea, pain, dizziness, andoedemawhich usually accompany carcinoid syndrome.Hill (I97 I) has reviewed the specific pharmacologicalapproaches to the treatment of carcinoid syndrome.

Reed, Kuipers, Vaitekevicius, Clark, Drake, andEyler (I963) had some success with antineoplasticagents (alkylating agents and antimetabolites) givenby hepatic artery infusion. Chemotherapy was notindicated in our patient because her lesion wassurgically accessible and she had no manifestations ofcarcinoid syndrome or evidence of any other meta-stases.

Malignant melanomas of the choroid have beentreated experimentally (Burns, Allen, and Fraun-felder, I 969) and clinically (Stallard, I 966) byirradiation of the lesion. However, preoperatively itwas considered more probable that the tumour in ourpatient was a metastatic carcinoid which is generallyconsidered to be radioresistant (Bargen, I96I; Brind-lev and Bonnet, I Q67; Davies, I 959; Goodner andothers, 196I; Holsti, I967; Reed and others, I963;Wilkins and others, x963). In certain instances highvoltage doses have been used on skin metastases withsome regression of the tumour. However, in mostcases ofcarcinoid, the results obtained with irradiationhave been disappointing, and there is no good evi-dence that radiotherapy is ofany value, other than forpossible palliation of bone pain (Martin, 1970). Inour case, the high doses of irradiation considerednecessary by the radiotherapists carried the risks ofdestruction of the eye and post-radiation sarcoma(Soloway, I966; Steiner, I965). Although the pos-sibility of local excision of tumours in the posteriorsegment of the choroid has recently been reported(Peyman, Nelsen, Axelrod, Graham, and Daily,1973), this technique is still regarded as experimental;and in our patient the tumour was located so near tothe macula that useful vision could probably not havebeen salvaged by excision. Enucleation was chosenbecause it offered the best long-term prognosis for thispatient.

SummaryThis report describes the clinical, light microscopical,and electron microscopical features of a metastasisfrom a bronchial carcinoid tumour occurring in a

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Solitary choroidal metastasis from bronchial carcinoid 163

29-year-old white woman. The eye lesions was metastasis was seen to be composed of cords; anddiagnosed 30 months after resection of the primary ribbons of cells which showed positive stainingpulmonary tumour. Ophthalmoscopically the patient characteristics for argentophilia. On electron micro-was observed to have a solid choroidal mass. Enuclea- scopical study, neurosecretory vesicles, numerous

tion was carried out because of the possibility that microvilli, mitochondria, and light and dark cells,the tumour was a primary choroidal melanoma. characteristic of endocrine tissue in different states ofEnucleation was also indicated because of the rela- activity were noted.tively good prognosis for long-term survival inpatients following excision of metastases from a The authors wish to thank Dr. Jackson Coleman of Col-bronchial carcinoid tumour. By light microscopy the umbia Presbyterian Hospital for the ultrasonography.

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